Discovery of aminopiperidine based potent & novel topoisomerase inhibitor with broad spectrum anti-bacterial activity.

Bacterial DNA gyrase and topoisomerase IV inhibition has emerged as a promising strategy for the cure of infections caused by antibiotic-resistant bacteria. The Novel Bacterial Topoisomerase Inhibitors (NBTIs) bind to a different site from that of the quinolones with novel mechanism of action. This evades the existing target-mediated bacterial resistance associated with quinolones. This article presents our efforts to identify in vitro potent and broad-spectrum antibacterial agent 4l.

Protective role of selenium and selenium-nanoparticles against multiple stresses in Pangasianodon hypophthalmus.

Pollution and climate change pose significant threats to aquatic ecosystems, with adverse impacts on aquatic animals, including fish. Climate change increases the toxicity of metal in aquatic ecosystems. To understand the severity of metal pollution and climate change, an experiment was conducted to delineate the mitigation potential of selenium (Se) and selenium nanoparticles (Se-NPs) against lead (Pb) and high temperature stress in Pangasianodon hypophthalmus. For the experiment, five isonitrogenous and isocaloric diets were prepared, varying in selenium supplementation as Se at 0, 1, and 2 mg kg-1 diet, and Se-NPs at 1 and 2 mg kg-1 diet. The fish in stressor groups were exposed to Pb (1/20th of LC50 concentration, 4 ppm) and high temperature (34 °C) throughout the experiment. The results demonstrated that dietary supplementation of Se at 1 and 2 mg kg-1 diet, as well as Se-NPs at 1 mg kg-1 diet, significantly reduced (p < 0.01) the levels of lactate dehydrogenase and malate dehydrogenase in both liver and muscle tissues. Additionally, the levels of alanine aminotransferase and aspartate aminotransferase in both gill and liver tissues were significantly decreased (p < 0.01) with the inclusion of Se and Se-NPs in the diets. Furthermore, the enzymes glucose-6-phosphate dehydrogenase in gill and liver tissues, fructose 1,6-bisphosphatase in liver and muscle tissues, and acid phosphatase in liver tissue were remarkably reduced (p < 0.01) due to the supplementation of Se and Se-NPs. Moreover, dietary supplementation of Se and Se-NPs significantly enhanced (p < 0.01) the activity of pyruvate kinase, glucokinase, hexokinase, alkaline phosphatase, ATPase, protease, amylase, lipase, and RNA/DNA ratio in the fish. Histopathological examination of gill and liver tissues also indicated that Se and Se-NPs protected against structural damage caused by lead and high-temperature stress. Moreover, the study examined the bioaccumulation of selenium and lead in muscle, water, and diets. The aim of the study revealed that Se and Se-NPs effectively protected the fish from lead toxicity and high-temperature stress, while also improving the function of cellular metabolic enzymes in P. hypophthalmus.

Optimisation of momelotinib with improved potency and efficacy as pan-JAK inhibitor.

Dysregulated JAK-STAT signaling has been proven to be involved in several immune-mediated diseases. Several janus kinase (JAK) inhibitors have been approved for the treatment of various inflammatory and autoimmune diseases such as rheumatoid arthritis (RA), plaque psoriasis, psoriatic arthritis, inflammatory bowel disease (IBD). Here, we report the design, optimisation, synthesis and biological evaluation of momelotinib analogues (a pyrimidine based JAK inhibitor), to get pan-JAK inhibitors. Systematic structure activity relationship studies led to the discovery of compound 32, which potently inhibited JAK1, JAK2 and JAK3. The in vivo investigation indicated that compound 32 possessed favourable pharmacokinetic properties and displayed superior anti-inflammatory efficacy than momelotinib 1. Accordingly, compound 32 was advanced into preclinical development.

Discovery of novel, potent and orally efficacious inhibitor of neutral amino acid transporter B0AT1 (SLC6A19).

Amino acid restriction by inhibition of neutral amino acid transporter, B0AT1 (SLC6A19) activity has been recently shown to improve glyceamic control by upregulating glucagon like peptide (GLP1) and fibroblast growth factor (FGF21) in mice. Hence, pharmacological inhibition of B0AT1 is expected to treat type-2 diabetes and related disorder. In this study, rationally designed trifluoromethyl sulfonyl derivatives were identified as novel, potent and orally bioavailable B0AT1 inhibitors. Compound 39 was found to be nanomolar potent (IC50: 0.035 µM) B0AT1 inhibitor with excellent pharmacokinetic profile (%F: 66) in mice and efficacious in vivo in diet induced obese (DIO) mice model.

Discovery of diaminopyrimidine-carboxamide derivatives as JAK3 inhibitors.

Selective inhibition of janus kinase (JAK) has been identified as an important strategy for the treatment of autoimmune disorders. Optimization at the C2 and C4-positions of pyrimidine ring of Cerdulatinib led to the discovery of a potent and orally bioavailable 2,4-diaminopyrimidine-5-carboxamide based JAK3 selective inhibitor (11i). A cellular selectivity study further confirmed that 11i preferentially inhibits JAK3 over JAK1, in JAK/STAT signaling pathway. Compound 11i showed good anti-arthritic activity, which could be correlated with its improved oral bioavailability. In the repeat dose acute toxicity study, 11i showed no adverse changes related to gross pathology and clinical signs, indicating that the new class JAK3 selective inhibitor could be viable therapeutic option for the treatment of rheumatoid arthritis.

Nano-copper Enhances Gene Regulation of Non-specific Immunity and Antioxidative Status of Fish Reared Under Multiple Stresses.

Arsenic pollution, water temperature, and pH are the major concern for aquaculture. Moreover, the aim of the present investigation was to delineate the role of nano-copper (Cu-NPs) in the mitigation of arsenic toxicity, high temperature (34 °C) and low pH (6.5) stress on Pangasianodon hypophthalmus. Four isonitrogenous and isocaloric experimental diets of Cu-NPs at 0, 1.0, 1.5 and 2.0 mg kg-1 were formulated and prepared. Arsenic pollution, low pH and high temperature stress significantly reduced the anti-oxidative status (super oxide dismutase, catalase, glutathione peroxidase and glutathione-s-transferase), lipid peroxidation, total anti-oxidative capacity and lipid profiling (cholesterol, total lipid, phospholipid, very low-density lipoprotein and triglyceride). Further, the supplementation of Cu-NPs at 1.5 and 1.0 mg kg-1 diets noticeably improve the anti-oxidant status and capacity. The stressors groups (As + pH + T, As + T and As) significantly reduced fish immunity viz. albumin, globulin, total protein, albumin globulin ratio (A:G ratio), myeloperoxidase, respiratory burst activities, tumor necrosis factor, total immunoglobulin, and interleukin. Whereas supplementation of Cu-NPs at 1.5 and 1.0 mg kg-1 diets improved the immunity of the fish reared under multiple stresses (As + pH + T). Tail DNA %, DNA damage-inducible protein (DDIP) and inducible nitric oxide (iNOS) synthase gene expression were significantly enhanced with exposure to arsenic, low pH and high temperature but supplementation of Cu-NPs protects the tissues against DNA damage and improved the gene expression of iNOS and DDIP. Cu-NPs at 1.5 and 1.0 mg kg-1 diets significantly enhanced the body weight gain %, protein efficiency ratio, specific growth rate, daily growth index, relative feed intake and reduced the feed conversion ratio. Whereas, the growth-related gene expression such as myostatin (MYST), somatostatin (SMT) was downregulated by Cu supplementation and upregulated the gene expression of growth hormone regulator 1 and ß (GHR1 and GHR ß) and growth hormone (GH) gene in fish. Dietary Cu-NPs supplementation protects the fish against bacterial infection and enhances arsenic detoxification in different tissues. The present investigation revealed that supplementation of Cu-NPs at 1.5 and 1.0 mg kg-1 diet has the potential to mitigate multiple stress (As + pH + T) in fish.

Synergistic effect of nickel and temperature on gene expression, multiple stress markers, and depuration: an acute toxicity in fish.

Aquatic animals are prone to extinction due to metal pollution and global climate change. Even though the fish and their products are also unsafe for human consumption, their exports have been rejected due to inorganic and organic contaminants. Nickel (Ni) is a metal that induces toxicity and accumulates in the aquatic ecosystem, posing health threats to humans, animals, and fish. In light of the above, our present investigation aimed to determine the median lethal concentration (96 h-LC50) of nickel alone and concurrent with high temperature (34 °C) (Ni + T) using static non-renewable bioassay toxicity test in Pangasianodon hypophthalmus. The groups treated under exposure to Ni reared under control condition (25-28.9 °C) and Ni + T exposure group reread under 34 °C. In this study, chose the definitive dose of Ni and Ni + T as 17, 18, 19, and 20 mg L-1 after the range finding test. The median lethal concentration of Ni and Ni + T was determined as 19.38 and 18.75 mg L-1, respectively at 96 h. Oxidative stress viz. catalase (CAT), superoxide dismutase (SOD), glutathione-s-transferase (GST), and glutathione peroxidase (GPx) in the liver, gill, and kidney were noticeably elevated with Ni and Ni + T during 96 h. Whereas, the CAT, GPx, and SOD gene expressions were significantly upregulated with Ni and Ni + T. Trilox equivalent anti-oxidant capacity (TEAC), cupric reducing anti-oxidant capacity (CUPRIC), ferric reducing ability of plasma (FRAP), ethoxy resorufin-O-deethylase (EROD), and acetylcholine esterase (AChE) were reduced due to exposure to Ni and Ni + T. Cellular metabolic stress and lipid peroxidation were highly affected due to Ni and Ni + T exposure. The immunological status, as indicated by total protein, albumin, globulin, A:G ratio, and nitro blue tetrazolium chloride (NBT), was severely affected by the toxicity of Ni and Ni + T. Moreover, the gene expression of interleukin (IL), tumor necrosis factor (TNFα), toll-like receptor (TLR), and total immunoglobulin (Ig) was remarkably downregulated following exposure to Ni and Ni + T. HSP 70, iNOS expression, ATPase, Na + /K + -ATPase, cortisol, and blood glucose was significantly elevated with Ni and Ni + T in P. hypophthalmus. The bioaccumulation of Ni in fish tissues and experimental water was determined. The kidney and liver tissues were highly accumulated with Ni, whereas DNA damage was reported in gill tissue. Interestingly, depuration study revealed that at the 28th day, the Ni bioaccumulation was below the maximum residue limit (MRL) level. Therefore, the present study revealed that Ni and Ni + T led to dysfunctional gene and metabolic regulation affecting physiology and genotoxicity. The bioaccumulation and depuration results also indicate higher residual occurrence of Ni in water and aquatic organisms for longer periods.

Nano­zinc enhances gene regulation of non­specific immunity and antioxidative status to mitigate multiple stresses in fish.

The toxicity of ammonia surged with arsenic pollution and high temperature (34 °C). As climate change enhances the pollution in water bodies, however, the aquatic animals are drastically affected and extinct from nature. The present investigation aims to mitigate arsenic and ammonia toxicity and high-temperature stress (As + NH3 + T) using zinc nanoparticles (Zn-NPs) in Pangasianodon hypophthalmus. Zn-NPs were synthesized using fisheries waste to developing Zn-NPs diets. The four isonitrogenous and isocaloric diets were formulated and prepared. The diets containing Zn-NPs at 0 (control), 2, 4 and 6 mg kg-1 diets were included. Superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione-s-transferase (GST) were noticeably improved using Zn-NPs diets in fish reared under with or without stressors. Interestingly, lipid peroxidation was significantly reduced, whereas vitamin C and acetylcholine esterase were enhanced with supplementation of Zn-NPs diets. Immune-related attributes such as total protein, globulin, albumin, myeloperoxidase (MPO), A:G ratio, and NBT were also improved with Zn-NPs at 4 mg kg-1 diet. The immune-related genes such as immunoglobulin (Ig), tumor necrosis factor (TNFα), and interleukin (IL1b) were strengthening in the fish using Zn-NPs diets. Indeed, the gene regulations of growth hormone (GH), growth hormone regulator (GHR1), myostatin (MYST) and somatostatin (SMT) were significantly improved with Zn-NPs diets. Blood glucose, cortisol and HSP 70 gene expressions were significantly upregulated by stressors, whereas the dietary Zn-NPs downregulated the gene expression. Blood profiling (RBC, WBC and Hb) was reduced considerably with stressors (As + NH3 + T), whereas Zn-NPs enhanced the RBC, WBC, and Hb count in fish reread in control or stress conditions. DNA damage-inducible protein gene and DNA damage were significantly reduced using Zn-NPs at 4 mg kg-1 diet. Moreover, the Zn-NPs also enhanced the arsenic detoxification in different fish tissues. The present investigation revealed that Zn-NPs diets mitigate ammonia and arsenic toxicity, and high-temperature stress in P. hypophthalmus.

Multi-biomarker approach to assess chromium, pH and temperature toxicity in fish.

Chromium (Cr) is considered as the most common ubiquitous pollutant for aquatic animals including fish. An experiment was conducted to determine the acute and chronic toxicity of Cr, pH and high temperature in Anabas testudineus. Lethal concentration (LC50) of Cr alone was determined as 55.02 mg L-1, Cr and low pH 48.19 mg L-1 and Cr, low pH and high temperature 47.16 mg L-1. The chronic toxicity of low dose of Cr, pH and high temperature (1/10th and 1/20th of LC50) was designed to execute the experiment for 72 days. The stress enzymes and biomarkers were determined viz. superoxide dismutase, catalase, glutathione peroxidase, glutathione-s-transferase, lipid peroxide, acetylcholine esterase, cortisol, HSP-70, blood glucose, aspartate amino transferase, alanine amino transferase and malate dehydrogenase, lactate dehydrogenase, ATPase and genotoxicity in this study. We had also studied the integrated biomarker response (IBR), which revealed that Cr toxicity enhanced with concurrent exposure to pH and high temperature. All the biochemical attributes were significantly altered with exposure to Cr alone and with low pH and high temperature except gill SOD. Further, thermal tolerance was also determined, and results revealed that thermal tolerance was significantly reduced with exposure to Cr alone and Cr and low pH exposure in A. testudineus. The present study concluded that, the chronic toxicity of Cr is enhanced with low pH and high temperature and it has led to understanding the multi-approach of Cr toxicity which affect, stress biomarkers, cellular metabolic stress and thermal tolerance of A. testudineus.

Selenium nanoparticles and omega-3 fatty acid enhanced thermal tolerance in fish against arsenic and high temperature.

The aquatic ecosystem is prone to global climate change and pollution affecting aquatic animals, including fish. In light of the above, we experimented with delineate the role of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) with selenium nanoparticles (Se-NPs) to enhance the thermal tolerance in Pangasianodon hypophthalmus reared under control or concurrent exposure to high temperature and arsenic (As + T) for 112 days. Se-NPs were synthesized using the green approach. Four experimental diets viz. EPA + DHA at 0.2, 0.4 and 0.6 % along with Se-NPs at 0.2 mg kg-1 diet were formulated and prepared. End of the experiment (112 days), the thermal tolerance viz. CTmin (critical thermal minima) CTmax (critical thermal maxima), LTmin (lethal thermal minima) and LTmax (lethal thermal maxima) were determined. Supplementation of EPA + DHA along with Se-NPs noticeably improved the thermal tolerance of the fish reared under stress (As + T) and control condition. Superoxide dismutase, glutathione-s-transferase, catalase, glutathione peroxides and LPO were enhanced by As + T, whereas EPA + DHA at 0.4 % and Se-NPs reduced the oxidative stress. Further, acetylcholine esterase was inhibited by arsenic alone and concurrent with temperature but dietary supplementation significantly enhanced the brain AChE activity. Exposure to arsenic and concurrent with a temperature significantly reduced the ATPase. Whereas supplementation of EPA + DHA at 0.4 % and Se-NPs enhanced the ATPase in liver and gill tissues. Arsenic bioaccumulation was also reduced with EPA + DHA at 0.4 % and Se-NPs. The present investigation concluded that EPA + DHA at 0.4 % and Se-NPs at 0.2 mg kg-1 diet protects the P. hypophthalmus against arsenic pollution and thermal stress.

Exploring mitigating role of zinc nanoparticles on arsenic, ammonia and temperature stress using molecular signature in fish.

BACKGROUND: The pollution and climate change in aquatic ecosystems are major problems threatening the aquatic organisms for existence in the recent timeline, which promotes the extinction of the fish species. However, the present study dealt with zinc nanoparticles (Zn-NPs) in mitigating arsenic, ammonia and high temperature stresses in Pangasianodon hypophthalmus. MATERIALS AND METHODS: To studying different gene expressions, an experiment was conducted to mitigate the multiple stressors using dietary Zn-NPs at 0, 2, 4, and 6 mg kg-1 diets. In the present investigation, the gene expressions studies were performed for growth hormone regulator 1 (GHR1), growth hormone regulator ß (GHRß), growth hormone (GR) in liver and gill tissue as well as myostatin (MYST) and somatostatin (SMT) in the muscle tissue. The anti-oxidative genes CAT, SOD and GPx in liver and gill tissues were also analysed. Expression studies for stress responsive heat shock protein gene (HSP70), DNA damage inducible protein, inducible nitric oxide synthase (iNOS), immune related genes such as interleukin (IL), tumour necrosis factor (TNFα), toll like receptor (TLR) and immunoglobulin were performed. At the end of the experiment the fish were infected with Aeromonas hydrophila to evaluate the immunomodulatory role of Zn-NPs. RESULTS: In the present investigation, the growth hormone regulator 1 (GHR1), growth hormone regulator ß (GHRß), growth hormone (GR) in liver and gill as well as myostatin (MYST) and somatostatin (SMT) in muscle were noticeably altered, whereas, Zn-NPs at 4 mg kg-1 diet improved gene expressions. The anti-oxidant gene viz. CAT, SOD and GPx in liver and gill tissues were upregulated by stressors such as As, NH3, NH3+T. As+T and As+NH3+T. Therefore, anti-oxidant genes were noticeably improved with dietary Zn-NPs diet. The stress protein gene (HSP70), DNA damage inducible protein, inducible nitric oxide synthase (iNOS) was significantly upregulated, whereas, Zn-NPs diet was applied to the corrected gene regulation. Similarly, immune related genes such as interleukin (IL), tumour necrosis factor (TNFα), toll like receptor (TLR) and immunoglobulin were highly affected by stressors. Dietary Zn-NPs at 4 mg kg-1 diet was improved all the immune related gene expression and mitigate arsenic, ammonia and high temperature stress in fish. CONCLUSION: The present investigation revealed that Zn-NPs at 4.0 mg kg-1 diet has enormous potential to modulates arsenic, ammonia and high temperature stress, and protect against pathogenic infections in fish.

Revisiting glitazars: thiophene substituted oxazole containing α-ethoxy phenylpropanoic acid derivatives as highly potent PPARα/γ dual agonists devoid of adverse effects in rodents.

In an effort to develop safe and efficacious compounds for the treatment of metabolic disorders, novel thiophene substituted oxazole containing α-alkoxy-phenylpropanoic acid derivatives are designed as highly potent PPARα/γ dual agonists. These compounds were found to be efficacious at picomolar concentrations. Lead compound 18d has emerged as very potent PPARα/γ dual agonist demonstrating potent antidiabetic and lipid lowering activity at a very low dose and did not exhibit any significant signs of toxicity in rodents.

Diaryl dihydropyrazole-3-carboxamides with significant in vivo antiobesity activity related to CB1 receptor antagonism: synthesis, biological evaluation, and molecular modeling in the homology model.

A number of analogues of diaryl dihydropyrazole-3-carboxamides have been synthesized. Their activities were evaluated for appetite suppression and body weight reduction in animal models. Depending on the chemical modification of the selected dihydropyrazole scaffold, the lead compounds--the bisulfate salt of (+/-)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid morpholin-4-ylamide 26 and the bisulfate salt of (-)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid morpholin-4-ylamide 30--showed significant body weight reduction in vivo, which is attributed to their CB1 antagonistic activity and exhibited a favorable pharmacokinetic profile. The molecular modeling studies also showed interactions of two isomers of (+/-)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid morpholin-4-ylamide 9 with CB1 receptor in the homology model similar to those of N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide (rimonabant) 1 and 4S-(-)-3-(4-chlorophenyl)-N-methyl-N'-[(4-chlorophenyl)-sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine (SLV-319) 2.